As expected, the FDA cleared for marketing Wednesday recombinant human C1 esterase inhibitor Ruconest (conestat alpha) for use in acute attacks of hereditary angioedema (HAE), news that should bring an immediate lift to developer Pharming Group NV – in the form of a $20 million milestone payment from partner Salix Pharmaceuticals Inc. due upon the first U.S. sale – but offers little clarity as to how the drug will stack up against well-entrenched competitors in the crowded HAE space.

Ruconest, approved for acute HAE attacks with the exception of laryngeal attacks, will be the fifth entrant in the orphan market – HAE affects from one in 10,000 to one in 50,000 people, or roughly 18,000 people in the U.S. and Europe. Already available to U.S. patients are the C1 esterase inhibitor Berinert from CSL Behring LLC, kallikrein inhibitor Kalbitor (ecallantide) from Dyax Corp. and bradykinin receptor antagonist Firazyr (icatibant) from Shire plc, all approved for acute HAE attacks.

Top-selling HAE drug, Cinryze, another C1 esterase inhibitor, is indicated for prophylactic use. Viropharma Inc. recorded Cinryze sales of $290 million for the first nine months of 2013; the following quarter, Dublin-based Shire made a $4.2 billion bid for Viropharma to nab rights to Cinryze. (See BioWorld Today, Nov. 12, 2013.)

Pharming's drug, meanwhile, hasn't made as much of a mark. Though it gained approval in Europe in late 2010 – where it's branded Rhucin – sales were slow to ramp up. In the first quarter of this year, Pharming posted revenues of only €900,000 (US$1.2 million) from sales by European partner Swedish Orphan Biovitrum AB, of Stockholm.

In the U.S., where it's been almost eight years since it received fast track designation, it faced a setback when the FDA declined to accept a marketing application in 2011, losing any advantage of being first to market. "Biotechnology companies for all sorts of reasons submit products for review prematurely," Pharming CEO Sijmen de Vries told BioWorld Today. "Pharming is no exception to that rule, unfortunately."

But perhaps most telling is the fact that Ruconest was a mere afterthought in Salix Pharmaceuticals Ltd.'s $2.6 billion buyout of Pharming's North American partner Santarus Inc. In fact, Carolyn Logan, president and CEO of Raleigh, N.C.-based Salix, told investors late last year that "we don't know a lot about [Ruconest] at this time." Combining the two companies' gastrointestinal products and sales strengths were the real drivers of that acquisition. (See BioWorld Today, Nov. 11, 2013.)

Salix hasn't offered much publicly in terms of its commercial plan for Ruconest, though, following the approval, the firm said it would make the drug "accessible to patients later in 2014."

Even though HAE is admittedly out of Salix's gastroenterology focus, Logan told investors during a February earnings call that the company certainly has the capacity to reach the small number of physicians treating HAE patients.

But Salix also has plenty of other items on its plate. Earlier this month, the firm's stock jumped on an update from the FDA that its subcutaneous version of opioid-induced constipation drug Relistor (methylnaltrexone bromide), partnered with Progenics Pharmaceuticals Inc., is approvable for chronic noncancer pain, which could more than double annual sales of Relistor. The company also is in the midst of big overseas move as it combines with Irish subsidiary of long-time collaborator Cosmo Pharmaceuticals SpA in an all-stock deal valued at $2.6 billion. (See BioWorld Today, July 10, 2014, and July 15, 2014.)

Shares of Salix (NASDAQ:SLXP) closed Thursday at $130.74, down $2.17.

Pharming shares moved in the opposite direction, albeit from a low base. The stock (AMSTERDAM:PHARM) peaked at €0.65 during trading Thursday, up 46 percent, before ending the day at €0.54, a gain of 17 percent on the previous close.

GIVING DOCTORS 'SOMETHING NEW'

It's anyone's guess how Ruconest will fare in the HAE market. Right now, Shire clearly is leading the pack, strengthened by its Viropharma buy. According to Cortellis Competitive Intelligence (CCI), average analyst forecasts put 2014 Cinryze sales at $480 million, while sales of Firazyr, which totaled $234.8 million in 2013, are expected to reach $329 million in full-year 2014 sales, based on consensus.

Sales of Dyax's Kalbitor have been far more modest by comparison. For 2013, sales reported by the Cambridge, Mass.-based company totaled $40.5 million. Consensus estimates compiled by CCI are expecting only a small increase in 2014 to $48 million.

No sales or forecast data were available for CSL's Berinert.

If Ruconest has any advantage over its fellow C1 esterase drugs, it's that it is a recombinant version of the human C1 protein inhibitor, whose improper function affects blood vessels and causes the rapid and sometimes dangerous swelling and inflammation characterized by HAE attacks. The other drugs are plasma-derived.

The FDA explicitly favors recombinant products over their plasma-derived counterparts, de Vries said, a position that does not prevail in Europe. Moreover, Ruconest may be in a position to differentiate itself on safety. The Cinryze and Berinert labels carry warnings of serious arterial and venous thromboembolic events, an issue that does not affect Ruconest, he said.

"We have never seen it in animals, and we have never seen it in patients," he said. "We have the beginnings of a differentiation on safety." It will take additional data to substantiate that claim, however, as the FDA considers the issue a class effect.

Ruconest, which has exactly the same amino acid sequence as endogenous human C1 inhibitor protein, is generated in the milk of transgenic rabbits, which, de Vries said, is another differentiator. "Unlike the plasma products, our cost of goods will go down with increased production," he said.

Joseph Pantginis, analyst at Roth Capital Partners, said he believes Ruconest "represents a serious threat" to Shire's HAE franchise, given that physicians will have an option of a recombinant product. "We believe docs will have something new to talk about," he wrote in a research report.

Leiden, the Netherlands-based Pharming expects revenues from Ruconest to hit about €3 million this year, but that forecast does not include U.S. sales. Should the product do well in the U.S., however, Pharming's partnership includes some favorable economics, Pantginis noted.

"For the first $100 million in sales, Pharming is entitled to 30 [percent] to 40 percent of net sales based on a combination of both royalties and drug supply to Salix," he said. If a proposed prophylactic study yields positive data, an expanded label in that setting would "pose a serious threat to Cinryze."

Before its acquisition, Santarus also had plans to test Ruconest in a prophylactic HAE study and indicated interest in expanding clinical development in acute pancreatitis. There has been no word yet on when or if those programs will launch.

MORE COMPETITION ON THE WAY

Meanwhile, other products for HAE are advancing. There's a subcutaneous version of Berinert in phase III trials for the prevention of HAE. A phase II study testing a subcutaneous formulation of Cinryze was halted last year, after Viropharma and partner Halozyme Therapeutics Inc. reported high levels of non-neutralizing antibodies. (See BioWorld Today, Aug. 2, 2013.)

Second-generation products also are in development already. Biocryst Pharmaceuticals Inc. wowed investors in May with a successful phase IIa proof-of-concept study, dubbed OPuS-1, with oral kallikrein inhibitor BCX4161, while Dyax disclosed positive phase I results in February with antibody DX-2930, a subcutaneous therapy in the kallikrein class, aimed at prophylactic use. Another kallikrein contender is Isis Pharmaceuticals Inc.'s antisense candidate ISIS-PKKRx, in phase I development. (See BioWorld Today, May 28, 2014.)